Mechanisms and implications of autonomic nervous system dysfunction in heart failure.

Abstract

Neurohumoral activation characterizes heart failure. Patients with the greatest amount of neurohumoral activation, as estimated by plasma norepinephrine levels, have the worst prognosis. The fundamental mechanisms underlying this neurohumoral activation remain unknown, however. Recent data support the hypothesis that early sympathetic dysregulation in heart failure is attributable to early attenuation of cardiac and arterial baroreceptor control of sympathetic nerve activity. Neurohumoral excitation is organ specific, affecting the heart first. Neurohumoral activation follows a stepwise pattern, with resistance to atrial natriuretic peptide and marked sympathetic activation characterizing a transition period from left ventricular dysfunction to overt heart failure. Renin-angiotensin-aldosterone system activation then occurs. Additional abnormalities of afferent systems, such as augmented muscle metaboreceptor sensitivity and increased peripheral chemoreceptor sensitivity, may modulate the sympathetic activation in established heart failure. Brain ouabainlike activity has been shown to cause sympathetic excitation in two animal models of heart failure and may play a key (although presently undefined) role in neurohumoral excitation in humans with heart failure. Therapies that interrupt, or even reverse, the neurohumoral activation in heart failure hold the greatest promise for the growing patient population afflicted with this syndrome.